Peripheral immune challenges elicit differential up-regulation of hippocampal cytokine and chemokine mRNA expression in a mouse model of the 15q13.3 microdeletion syndrome


The hippocampus is a small, curved structure located deep within the brain, specifically in the medial temporal lobe. It plays a crucial role in various cognitive functions and is widely recognized for its importance in memory formation and spatial navigation.  The hippocampus is implicated in several diseases and conditions, particularly those that affect memory and cognitive function including Alzheimer’s Disease, epilepsy, Major Depressive Disorder and Schizophrenia.  Interestingly, these disorders have also been associated with genetic variations that affect the expression or function of NF-κB or its target genes. One such genetic variation is the 15q13.3 microdeletion syndrome, which is caused by a deletion of a segment of chromosome 15 that spans at least seven genes, including CHRNA7, which encodes a subunit of the nicotinic acetylcholine receptor (nAChR). This receptor is involved in cholinergic signaling, which modulates neuronal excitability and synaptic plasticity. The 15q13.3 microdeletion syndrome is associated with a wide range of phenotypes, such as intellectual disability, epilepsy, ASDs, schizophrenia, and bipolar disorder. However, the molecular mechanisms underlying the pathophysiology of this syndrome are not well understood. Moreover, the relationship between 15q13.3 microdeletion syndrome and the hippocampus is not well understood. Currently, there is limited specific research on how this genetic deletion affects the hippocampus directly.  Considering the cognitive and neurodevelopmental features commonly associated with 15q13.3 microdeletion syndrome, it is plausible that the hippocampus could be indirectly affected. Some of the neurodevelopmental characteristics often observed in individuals with the syndrome, such as intellectual disability, developmental delays, and autism spectrum disorder (ASD)-like symptoms, can be associated with alterations in hippocampal structure and function. Moreover, seizures and epilepsy, which are prevalent in 15q13.3 microdeletion syndrome, can also impact the hippocampus. Seizure activity originating from the hippocampus itself or affecting this brain region can disrupt normal hippocampal function and potentially lead to cognitive impairments

In a new study published in the peer-reviewed journal Cytokine, Kristin McCamy, Katherine Rees, and led by Associate Professor Ursula Winzer-Serhan from Texas A&M Health Science Center investigated the expression of neuroinflammatory markers in the hippocampus of the 15q13.3 heterozygous mouse model in response to a low dose of the viral mimetic polyinosinic:polycytidylic acid Poly(I:C) and compared the results with those obtained with lipopolysaccharide LPS. Additionally, the researchers analyzed the mRNA expression levels of selected chemokines including interferon beta (INFβ) and IFNγ, which play an tole in innate and adaptive immunity, as well as markers for astrocytic and microglial activation, GFAP and Iba1, respectively. Furthermore, the study examined treatment-induced sickness behavior through the burrowing test, a hippocampus-dependent behavioral task that is highly sensitive to cytokine disruption, to understand how immune stimulation affects sickness behavior at the molecular level.

The activation of the innate immune system transmits signals to the brain that elicit sickness behavior. The study examined the effects of low doses of LPS and Poly(I:C) on the expression of cytokines and chemokines and sickness behavior in mice, with room for differential responses by genotype. The authors showed that LPS reduced overnight burrowing, but Poly(I:C) did not affect burrowing in any group. However, both LPS and Poly(I:C) increased hippocampal expression of cytokines and chemokines. LPS was more potent in stimulating pro-inflammatory cytokines and chemokines than Poly(I:C), although both had a similar induction pattern of transcripts. The lower induction of cytokines by Poly(I:C) may have been insufficient to cause sickness despite increased expressions of chemokines. The study demonstrated that an acute peripheral immune challenge with low dose Poly(I:C) provokes a rapid increase in expression of cytokines and chemokines in both sexes and genotypes without overt sickness behavior. The study also examined the effects of the 15q13.3 microdeletion on immune functions and found little or no regulatory role of α7 nAChRs in LPS-induced TNF-α expression, although reduced astrocytic α7 nAChR expression could diminish anti-inflammatory α7-mediated functions resulting in genotype effects for IL-1β, IL-6, CXCL1, CCL4, and CCL5 following a peripheral LPS immune challenge. The study also found that LPS induced a genotype-dependent increase in IL-1β expression, which could be responsible for genotype effects seen for CXCL1, CCL4, and CCL5 expression in the hippocampus. The study demonstrated that during an innate immune response, levels of cytokines and chemokines are increased even in the absence of symptoms of sickness. Future studies will determine if elevated levels result in increased seizure susceptibility in Het mice.

In summary, the current study suggests that individuals with the 15q13.3 deletion syndrome may have increased neuroimmune responses, which could potentially drive hyperexcitability in the brain. This hyperexcitability, combined with altered excitatory/inhibitory synaptic transmission, could be linked to various neurological disorders, including autism, schizophrenia, and seizures. Therefore, increased sensitivity to neuroimmune modulators may provide a common mechanism underlying the variable neurological phenotypes associated with the 15q13.3 microdeletion. Further research is needed to fully elucidate the mechanisms underlying this relationship and its implications for brain function and health.


McCamy KM, Rees KA, Winzer-Serhan UH. Peripheral immune challenges elicit differential up-regulation of hippocampal cytokine and chemokine mRNA expression in a mouse model of the 15q13. 3 microdeletion syndrome. Cytokine. 2022 ;159:156005.

Go To Cytokine.